Long-term impact of paediatric critical illness on the difference between epigenetic and chronological age in relation to physical growth

Abstract

Background Altered DNA-methylation affects biological ageing in adults and developmental processes in children. DNA-methylation is altered by environmental factors, trauma and illnesses. We hypothesised that paediatric critical illness, and the nutritional management in the paediatric intensive care unit (PICU), affects DNA-methylation changes that underly the developmental processes of childhood ageing. Results We studied the impact of critical illness, and of the early use of parenteral nutrition (early-PN) versus late-PN, on “epigenetic age-deviation” in buccal mucosa of 818 former PICU-patients (406 early-PN, 412 late-PN) who participated in the 2-year follow-up of the multicentre PEPaNIC-RCT (ClinicalTrials.gov-NCT01536275), as compared with 392 matched healthy children, and assessed whether this relates to their impaired growth. The epigenetic age-deviation (difference between PedBE clock-estimated epigenetic age and chronological age) was calculated. Using bootstrapped multivariable linear regression models, we assessed the impact hereon of critical illness, and of early-PN versus late-PN. As compared with healthy children, epigenetic age of patients assessed 2 years after PICU-admission deviated negatively from chronological age (p < 0.05 in 51% of bootstrapped replicates), similarly in early-PN and late-PN groups. Next, we identified vulnerable subgroups for epigenetic age-deviation using interaction analysis. We revealed that DNA-methylation age-deceleration in former PICU-patients was dependent on age at time of illness (p < 0.05 for 83% of bootstrapped replicates), with vulnerability starting from 6 years onwards. Finally, we assessed whether vulnerability to epigenetic age-deviation could be related to impaired growth from PICU-admission to follow-up at 2 and 4 years. Multivariable repeated measures ANOVA showed that former PICU-patients, as compared with healthy children, grew less in height (p = 0.0002) and transiently gained weight (p = 0.0003) over the 4-year time course. Growth in height was more stunted in former PICU-patients aged ≥ 6-years at time of critical illness (p = 0.002) than in the younger patients. Conclusions As compared with healthy children, former PICU-patients, in particular those aged ≥ 6-years at time of illness, revealed epigenetic age-deceleration, with a physical correlate revealing stunted growth in height. Whether this vulnerability around the age of 6 years for epigenetic age-deceleration and stunted growth years later relates to altered endocrine pathways activated at the time of adrenarche requires further investigation.

Abnormal DNA methylation within genes of the steroidogenesis pathway two years after paediatric critical illness and association with stunted growth in height further in time

“…Age dependency of vulnerability towards abnormal DNA methylation was somewhat greater, with a more pronounced hypomethylation of several CpG sites within HSD17B2 , HSD17B12 and CYP19A1 in children who at the time of PICU admission had already reached or passed the age of adrenarche as compared with younger children. This corresponds with our earlier finding of a higher vulnerability to epigenetic age deceleration of former PICU patients from the age of adrenarche onwards and into puberty [ 11 ].…”

“…For the differentially methylated positions in former PICU patients as compared with healthy children, we assessed whether there was an interaction with sex and/or age at exposure to critical illness and its treatments. We recently found that vulnerability to age deceleration of former PICU patients as compared with healthy children started from ± 6 years at exposure to critical illness and its treatments [ 11 ]. Therefore, we dichotomised age accordingly for the age-interaction analyses.…”

“…The age deceleration that we had documented in former critically ill children 2 years after PICU admission, as compared with normally developing healthy children, had a physical correlate in the form of stunted growth in height 2 years further in time [ 11 ]. Therefore, we investigated whether methylation status in former PICU patients associated with height at 4-year follow-up.…”

“…The mechanisms explaining adverse long-term outcomes after critical illness remain largely unclear, but epigenetic abnormalities induced by critical illness or associated treatments have been suggested as a plausible molecular basis [ 9 ]. Interestingly, estimation of “epigenetic” or biological age, with an epigenetic clock developed for children on buccal mucosa DNA [ 10 ], revealed an age deceleration in former critically ill children 2 years after PICU admission, as compared with normally developing healthy children, with stunted growth in height 2 years further in time as a physical correlate [ 11 ]. Vulnerability towards epigenetic age deceleration, interpreted as a developmental delay, was particularly observed from the age of 6 years onwards at the time of critical illness.…”

Early weight measures and long-term neuropsychological outcome of critically ill neonates and infants: a secondary analysis of the PEPaNIC trial

“…In previous studies in infants with congenital heart disease, impaired height trajectories were associated with worse neurodevelopmental outcomes [ 55 , 56 ]. However, head circumference at birth, postnatal factors, genetic comorbidity, and epigenetic changes are important factors which must be taken into account concerning impaired height trajectories and neuropsychological outcome [ 61 ]. Also, when evaluating outcome of children after PICU discharge, it is important to include baseline (health) status and family factors in multifactorial predictive models [ 62 , 63 ].…”